Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 209, Issue 12, Pages 2247-2261Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20120831
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- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- National Cancer Institute
- Uniformed Services University of Health Sciences
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Nuclear factor-kappa B (NF-kappa B) controls genes involved in normal lymphocyte functions, but constitutive NF-kappa B activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)-induced NF-kappa B activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-kappa B activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.
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